Benjamin de Haas explains individual differences in eye movement patterns.
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Edited* by Tony Hunter, The Salk Institute for Biological Studies, La Jolla, CA, and approved December 31, 2009 (received for review August 19, 2009)
Abstract
Kinases are known to regulate fundamental processes in cancer including tumor proliferation, metastasis, neovascularization, and chemoresistance. Accordingly, kinase inhibitors have been a major focus of drug development, and several kinase inhibitors are now approved for various cancer indications. Typically, kinase inhibitors are selected via high-throughput screening using catalytic kinase domains at low ATP concentration, and this process often yields ATP mimetics that lack specificity and/or function poorly in cells where ATP levels are high. Molecules targeting the allosteric site in the inactive kinase conformation (type II inhibitors) provide an alternative for developing selective inhibitors that are physiologically active. By applying a rational design approach using a constrained amino-triazole scaffold predicted to stabilize kinases in the inactive state, we generated a series of selective type II inhibitors of PDGFRβ and B-RAF, important targets for pericyte recruitment and endothelial cell survival, respectively. These molecules were designed in silico and screened for antivascular activity in both cell-based models and a Tg(fli1-EGFP) zebrafish embryogenesis model. Dual inhibition of PDGFRβ and B-RAF cellular signaling demonstrated synergistic antiangiogenic activity in both zebrafish and murine models of angiogenesis, and a combination of previously characterized PDGFRβ and RAF inhibitors validated the synergy. Our lead compound was selected as an orally active molecule with favorable pharmacokinetic properties which demonstrated target inhibition in vivo leading to suppression of murine orthotopic tumors in both the kidney and pancreas.
Footnotes
- 1To whom correspondence should be addressed. E-mail: dcheresh{at}ucsd.edu.
-
Author contributions: E.A.M., D.J.S., M.B., W.W., and D.A.C. designed research; E.A.M., D.J.S., K.S., E.D., M.M., J.I.G., J.L., L.M.A., S.A., B.K.M., I.T., A.S., and B.W. performed research; E.A.M., D.J.S., J.I.G., R.M.H., R.L.K., P.K.V., L.A., W.W., and D.A.C. analyzed data; and E.A.M. and D.A.C. wrote the paper.
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↵*This Direct Submission article had a prearranged editor.
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The authors declare no conflict of interest.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0909299107/DCSupplemental.
- Eric A. Murphy a,
- David J. Shields a,
- Konstantin Stoletov a,
- Elena Dneprovskaia b,
- Michele McElroy c,
- Joshua I. Greenberg c,
- Jeff Lindquist a,
- Lisette M. Acevedo a,
- Sudarshan Anand a,
- Bharat Kumar Majeti a,
- Igor Tsigelny d,
- Adrian Saldanha e,
- Breda Walsh a,
- Robert M. Hoffman c, f,
- Michael Bouvet c,
- Richard L. Klemke a,
- Peter K. Vogt g,
- Lee Arnold h,
- Wolfgang Wrasidlo a, and
- David A. Cheresh a, 1
- aDepartment of Pathology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093;
- bTargeGen Inc., San Diego, CA 92121;
- cDepartment of Surgery, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093;
- dDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093;
- eDepartment of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093;
- fAnticancer Inc., San Diego, CA 92111;
- gDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037; and
- hKinagen Inc., Encinitas, CA 92024
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Edited* by Tony Hunter, The Salk Institute for Biological Studies, La Jolla, CA, and approved December 31, 2009 (received for review August 19, 2009)
Abstract
Kinases are known to regulate fundamental processes in cancer including tumor proliferation, metastasis, neovascularization, and chemoresistance. Accordingly, kinase inhibitors have been a major focus of drug development, and several kinase inhibitors are now approved for various cancer indications. Typically, kinase inhibitors are selected via high-throughput screening using catalytic kinase domains at low ATP concentration, and this process often yields ATP mimetics that lack specificity and/or function poorly in cells where ATP levels are high. Molecules targeting the allosteric site in the inactive kinase conformation (type II inhibitors) provide an alternative for developing selective inhibitors that are physiologically active. By applying a rational design approach using a constrained amino-triazole scaffold predicted to stabilize kinases in the inactive state, we generated a series of selective type II inhibitors of PDGFRβ and B-RAF, important targets for pericyte recruitment and endothelial cell survival, respectively. These molecules were designed in silico and screened for antivascular activity in both cell-based models and a Tg(fli1-EGFP) zebrafish embryogenesis model. Dual inhibition of PDGFRβ and B-RAF cellular signaling demonstrated synergistic antiangiogenic activity in both zebrafish and murine models of angiogenesis, and a combination of previously characterized PDGFRβ and RAF inhibitors validated the synergy. Our lead compound was selected as an orally active molecule with favorable pharmacokinetic properties which demonstrated target inhibition in vivo leading to suppression of murine orthotopic tumors in both the kidney and pancreas.
- type II inhibitor
- kinase inhibition
- pancreatic carcinoma
- pericyte
- cell-based screening
Footnotes
- 1To whom correspondence should be addressed. E-mail: dcheresh{at}ucsd.edu.
-
Author contributions: E.A.M., D.J.S., M.B., W.W., and D.A.C. designed research; E.A.M., D.J.S., K.S., E.D., M.M., J.I.G., J.L., L.M.A., S.A., B.K.M., I.T., A.S., and B.W. performed research; E.A.M., D.J.S., J.I.G., R.M.H., R.L.K., P.K.V., L.A., W.W., and D.A.C. analyzed data; and E.A.M. and D.A.C. wrote the paper.
-
↵*This Direct Submission article had a prearranged editor.
-
The authors declare no conflict of interest.
-
This article contains supporting information online at www.pnas.org/cgi/content/full/0909299107/DCSupplemental.
Disruption of angiogenesis and tumor growth with an orally active drug that stabilizes the inactive state of PDGFRβ/B-RAF
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